Structural and biophysical characterisation of insulin receptor and glutamate receptors AMPAR and NMDAR in complex with SorCS coreceptors 1 and 2

Type II diabetes (T2D), Alzheimer’s Disease (AD) and Parkinson’s disease (PD) are common age-related diseases, which have reached endemic levels and become a burden for the global health. Lifestyle and environment are risk factors, but cannot explain all cases - genes also predispose for these diseases.

Common for T2D, AD and PD is abnormal cell function associated with dysfunction of insulin receptor, AMPA receptor or NMDA receptor.

The Vacuolar Protein Sorting 10 protein (VPS10P) family contain five neural type 1 transmembrane sorting receptors: sortilin, SorLA, SorCS1, SorCS2 and SorCS3, that play a central role in control of neuronal viability and function by sorting crucial proteins.

SorCS1 and SorCS2 interact with and sort IR, AMPAR and NMDAR, and genetic deficiencies for SorCS1 and -2 are associated with accelerated onset of pathology, thus implicating these receptors as critical regulators for normal cell function.

However, the molecular mechanisms of SorCS1 and SorCS2 mediated sorting of target receptors are not known, and with this proposal I want to determine structures and investigate interactions of SorCS1:IR, SorCS1:AMPAR and SorCS2:NMDAR complexes.

Determining the structures of transmembrane SorCS1:IR, SorCS1:AMPAR and SorCS2:NMDAR complexes by cryogenic electron microscopy (cryo-EM) we will reveal molecular details about the interaction such as the role of interacting elements at cytoplasmic tails, transmembrane helices and exodomains, and how they define specificity (SorCS1 vs.

SorCS2), function and regulation.

The proposed project can define new positions and in translational research that aims for drug discovery for T2D, AD and PD.